CHEM 234: Organic Chemistry II Reaction Sheets

Transcription

1 EM234:rganichemistry eactionsheets ucleophilic addition at carbonyl groups: Grignards and reducing agents u: u u u: u u = or = or l u u u ucleophilic addition at carbonyl groups: oxygen and nitrogen nucleophiles: acyl exchange u: u u =, l For =, reactions are generally reversible with u = and can occur under acidic or basic conditions. f u =, reaction is generally irreversible due to deprotonation of the product acid. ucleophilic addition at carbonyl groups: xygen and nitrogen nucleophiles, = or 2, = or 2, = or

2 Enol and enolate formation Base acid or base = or 2, 2 ' 2 General reactions of enolates

3 eductions of aldehydes and ketones. ab 4 M or LiAl 4 acidic workup M ab 4 acidic workup or LiAl 4 Li 3 LiAl 4 Al 3 3 LiAl 3 (Me) LiAl 4 Barbier reaction (1899) 1. 3, Mg 2. Acid workup Grignard reaction (1900) 1. 3 Mg 3 Mg 2. Acid workup Grignard reagent 1. Mg Mg 2. Acid workup

4 Grignard additions and reductions of esters. Mg 3 Mg 3 3 MeMg Mg Mg Mg 3 workup 3 3 Synthesis and reactions of epoxides: Me Me, Me Me Me Mea Me Me Mg will give similar opening ( replaces Me)

5 Formation of alkyl halides from alcohols 3 Alcohols - dry or l 1 Alcohols - P 3 or Sl 2 P 3 Me 3 Si Me PPh 3 Me 3 Si Me xidation of alcohols 2 r 4 acetone 2 r 4 acetone P 2 l hemiacetal (unstable) 3 acetal (stable) 3 2 hemiaminal An imine

6 2 The Wittig reaction An enamine PPh 3 PPh3 PPh 3 n-buli PPh 3 Li PPh 3 unstablized ylides give cis 3 Ph 3 P Me Me stabilized ylides give trans orner-wadsworth-emmons reaction: A Wittig variant base Et P Me Et To generate enolates, use strong base. Et P Et Me Me 3 a a 3 3 Li a 3

7 3 The aloform eaction ad D 2 2 D D 3 3 a a 2 2 The Aldol eaction a a 2 rossed aldol reactions. Practical when one component contains no!-hydrogens Ketones: equilibrium unfavourable a a Dehydration is also very common in acid catalyzed aldol reactions. 2 l 2

8 ntramolecular aldol: cyclizations to form rings. a or l a or l The use of strong base is advantageous for directed aldol reactions Li Li i Pr 2 Li Ph mild acid workup Strong base is also useful for generating enolates of esters and amides. i Pr 2 Li Li 78 pka ~ i Pr 2 Li Li 78 pka ~ 27-28

9 Additional uses of lithium enolates: alkylation Li i Pr 2 Li % Michael additions work well when only one component can enolize and one component can undergo addition 45% Good reaction: 2 Li t-bu i Et t-bu Pr 2 Li t-bu 78 Li t-bu i Et t-bu Pr 2 Li t-bu 78 Poor reaction: Many possible combinations t-bu t-bu Et Et t-bu t-bu Poor reaction: Many possible combinations aet obinson Annulation aet aet 65% yield Sir obert obinson obel 1947 Most classic obinson annulations use!-diketones as they direct the reaction better. Et a 2 Ph 43% yield

10 a 2 Ph 43% yield Ph Ac, aac benzene reflux 2, reflux Synthesis of esters from alcohols and carboxylic acids: esterification Saponification: irreversible hydrolysis of an ester 3 3 a 3 a 3 Sl 2 l Pl 3 and Pl 5 accomplish the same reaction Acid chlorides and anhydrides react with alcohols to form esters. base l base

11 Amines react easily with acid chlorides and anhydrides to form amides. atalysts are not generally needed. l Et 3 2 Et 3 Acid blocking groups: esters 3 3 3, Me a l 3 3 Amine blocking groups: carbamates Most common example: the tert-butyloxycarbonyl group (Boc) 3 3 a, dioxane/ 2 F 3 2 3

12 Dipeptide synthesis: 3 l 3 3 D, Et 3 (Bt) 3 3 Although acid chloride or acid anhydrides might be used in theory, in practice they lead to some racemization of the acid component. We thus use D or other carbodimides, sometimes in combination with Bt or other nucleophiles. 1. a 2. F Dicyclohexylcarbodiimide (D) and -hydroxybenzotriazole (Bt) in amide formation. 2 ' (D) (Bt) Acid hydrolysis of amides is very slow. ommon conditions 6 M l ' 3 ' slow ' " " ydrolysis of nitriles produces 1 amides or carboxylic acids. 3 2

13 itriles are more conveniently prepared by nucleophilic reactions: alide displacement S 2 a onjugate addition a Formation of cyanohydrins a Formation of an!-aminonitrile ' ' 2 ydrolysis of nitriles produces 1 amides or carboxylic acids. 3 2

14 laisen ondensation Esters are enolized by weaker bases. f we have a methyl ester, we use sodium methoxide so that transesterifcation is redundant. Mea a Mea acid workup a Mea a Mea acid workup a Mea a rossed laisen condensations are sometimes difficult to carry out. As with aldol, they work out well if one component has no!-hydrogens. Mea o thermodynamic sink Mea a Mea a acid workup ntramolecular laisen condensation: Dieckmann condensation Me Me Mea Me a Me Me Mea Me a acid workup

15 omparison of simple ketone alkylation vs. acetoacetic ester method aet K a heat LDA LDA Malonic esters have similar chemistry to acetoacetates Et Et aet Et Ph Et K Et Ph Et Et Et a heat Ph Ph 2 Ph

16 Synthesis of amines Simple S 2 displacement of alkyl halides Synthesis of amines Azide is a good replacement for ammonia in a simple S2. a 3 LiAl 4 or Ph 3 P, 2 2 Gabriel synthesis: Phthalimide as an ammonia equivalent. K K 2 2 2

17 eductive amination Et 2 LiAl 4 ab 3 Ac eductions of nitriles and amides LiAl 4 or B 3 LiAl 4 or B 3 Primary amines from amides via offman and urtuis rearrangement a a 3 l heat, 2 2

18 Diazotization 2 a 2 2 S 4 S 4 arenediazonium ion Arenediazonium ions are more stable (up to 5 ) and are synthetically useful. Sandmeyer reaction Y u = l,, Also u 2 to get = 2 a 2 2 S 4 S 4 P Alkyl diazonium ions mainly useful in amino acids. 2 Azo compounds by diazo coupling. a 2, 2 S 4 a Me 2 Me 2 a 2 l 2 l aac ofmann elimination gives different regioselectivity compared to normal eliminations. 3 Ag 2 2 Me 3 ame heat

19 The Mannich reaction is a good way to install methylene groups adjacent to ketones. Me; a n some cases, aryl halides can undergo displacement with nucleophiles. l a 350 l 2 a l 2 a l 2 a